URINARY BLADDER-SELECTIVE ACTION OF THE NEW ANTIMUSCARINIC COMPOUND VAMICAMIDE

1. The inhibitory action of vamicamide (FK176, )-(2R,4R*)-4-dimethyla mino-2-phenyl-2-(2-pyridyl) valeramide, CAS 132373-81-0) on the respon ses of various tissues to the cholinergic agonists, carbachol and McN- A-343 lorophenylcarbamoyloxy]-2-butynyltrimethylammonium chloride, CAS 55-45-8), was investigated in isolated tissue preparations. Vamicamid e showed competitive antagonist actions against all the preparations t ested and its pA(2) value for the urinary bladder was 6.82, which was higher than that for the atria (5.94) and almost the same as that for the vas deferens (6.90) and for the stomach (6.81). The pA(2) values o f oxybutynin hydrochloride (oxybutynin) and atropine sulfate monohydra te (atropine) were nearly the same in all the tissues tested. 2. Oral administration of vamicamide 0.1-1.0 mg/kg inhibited dose-dependently spontaneous bladder contractions caused by raising the intravesical vo lume in conscious rats. Inhibitory actions were also obtained with 0.3 2-3.2 mg/kg of oxybutynin or 0.0032-0.032 mg/kg of atropine, but the d uration of action of oxybutynin was shorter than that of vamicamide or atropine. Vamicamide further inhibited bladder contractions in rats f ollowing intravesical administration of 0.05-0.5 mg/ml solution. 3. Va micamide had no effect or only slightly inhibited spontaneous motility of the stomach and distal colon in conscious rats, as well as heart r ate and salivary secretion in conscious dogs, after oral dosing with 3 .2 mg/kg of the compound. Similar results were obtained with oxybutyni n, exceptin g the occurrence of tachycardia. 4. Vamicamide had no effe ct at all on oxotremorine-induced tremor in mice after oral dosing wit h 0.32-320 mg/kg, while oxybutynin depressed tremor at oral doses of 3 2 mg/kg or more. 5. In rates treated i.v. with C-14-vamicamide 1 mg/kg , the ratios of radioactivity measured in the brain to that in the pla sma till 4 h after dosing were from 0 to only 0.19, while the ratios a fter dosing with C-14-oxybutynin 1 mg/kg were from 1.58 to 3.70. 6. Th e ratios of radioactivity in the urinary bladder to that in the plasma were from 2.22 to 73.22 after i.v. dosing with C-14-vamicamide, which were higher than those (from 0.59 to 13.02) for C-14-oxybutynin.